High dose therapy followed by allogeneic bone marrow transplantation (BMT) is associated with high response rates in patients with multiple myeloma but few, if any, patients remain disease free for prolonged periods after transplantation. Allogeneic stem cell transplantation is further limited by excessive toxicity which appears to be higher in patients with myeloma compared to other hematologic malignancies. In Specific Aim 1 we will use CD6 T cell depleted allogeneic BMT to reduce graft-versus-host disease (GVHD) and subsequently utilize selective infusion of CD4+ donor lymphocytes to augment GVM immunity after transplant. Preliminary results suggest that CD6 T cell depletion effectively reduces the incidence of GVHD in patients with myeloma, thereby eliminating the need for prophylactic immune suppression in the vast majority of myeloma patients undergoing BMT. Elimination of prophylactic immune suppression coupled with the reduction in GVHD appears to markedly reduce transplant-related mortality in the first year post-BMT. Preliminary clinical studies also indicate that selective infusion of normal CD4+ donor lymphocytes (obtained after CD8 depletion of donor cells ex vivo) results in substantial anti-myeloma activity in patients with relapsed myeloma after allogeneic BMT. With this preliminary experience we have already initiated a clinical trial combining these approaches in the treatment of patients with myeloma. In Specific Aim 2, we will further characterize the immunologic mechanism and specificity of the GVM response in patients enrolled on the clinical trials described in Specific Aim 1. Laboratory experiments in Specific Aim 2 will focus on a detailed examination of T cell repertoire, assessed by Vbeta T cell receptor gene rearrangement, to identify clonal T cells associated with graft-versus-myeloma effect and identify potential target antigens on tumor cells. The specificity of the GVM response in vivo will also be examined through serial analysis of hematopoietic chimerism following DLI. The results of these studies will lay the ground work for ex vivo expansion of myeloma specific T cells for use in trials of adoptive immunotherapy after allogeneic transplant detained in Specific Aim 3. These antigen specific adoptive immunotherapies will be combined with immunization strategies developed using autologous myeloma cells (to be developed in Projects 2 and 3) in order to effectively eliminate residual myeloma cells post allogeneic transplant.